quetiapine-fumarate and Opioid-Related-Disorders

Opioid poisoning is a frequent cause of death in drug addicts and occurs with opioid treatment. Quetiapine is often found in forensic autopsies and may increase the risk of fatal opioid poisoning by enhancing sedation, respiratory depression, hypotension and QT prolongation. We systematically searched for studies of acute toxicity of quetiapine or other antipsychotics combined with morphine or methadone. Case reports describing toxicity of quetiapine combined with morphine or methadone were also included. We retrieved one human study that observed pharmacokinetic interaction between quetiapine and methadone, and 16 other human studies. Fourteen investigated the combination of droperidol and morphine in treatment doses, and some indicated an additive sedative effect. Five animal studies with acepromazine in combination with morphine or methadone were located and indicated an additive effect on sedation and hypotension. Six forensic case reports in which death could have been caused solely by quetiapine, the opioid, or other drugs were found. Thus, acute toxicity of quetiapine combined with morphine or methadone has not been studied. Because of quetiapine's effects on alpha-adrenoceptors, muscarinic and histamine receptors, human ether-a-go-go-channels and methadone kinetics, we suggest further research to clarify if the indicated additive effects of opioids and droperidol or acepromazine are also true for quetiapine.

Topics: Adolescent; Adult; Analgesics, Opioid; Animals; Antipsychotic Agents; Arrhythmias, Cardiac; Autopsy; Cause of Death; Consciousness; Drug Interactions; Drug Overdose; Female; Forensic Toxicology; Humans; Hypotension; Male; Methadone; Middle Aged; Morphine; Opioid-Related Disorders; Quetiapine Fumarate; Respiratory Insufficiency; Risk Assessment; Risk Factors

Steady-state plasma concentrations of (R)- (ie, the active form), (S)-, and (R,S)-methadone were measured in 14 addict patients in methadone maintenance treatment, before and after introduction of quetiapine, administered at a mean dosage of 138 mg/d (SD, 87 mg/d; median, 125 mg/d; range, 50-300 mg/d) during a mean period of 30 days (SD, 8 days; median, 30 days; range, 20-48 days). Eleven patients were genotyped as being CYP2D6 extensive metabolizers (EMs) and 3 patients as poor metabolizers. Eleven patients had the ABCB1 3435 CT or CC genotypes, and 3 patients had the ABCB1 3435 TT genotype, the latter genotype being associated with lower P-glycoprotein activity. Quetiapine significantly increases (R)-methadone concentration-dose ratios in the whole group [increase for (R)-methadone: mean, +21%; SD, +28%; median, +13%; range, -23% to +85%; P = 0.026], but not for (S)-methadone (mean, +23%; SD, +43%; median, +6%; range, -30% to +115%; P = 0.12) or for (R,S)-methadone (mean, +21%; SD, +34%; median, +9%; range, -21% to +95%; P = 0.064). The mean increases of (R)-methadone concentration-dose ratios were of 7%, 21%, and 30% in the CYP2D6 poor metabolizers, heterozygous EMs, and homozygous EMs, respectively, whereas they were of 3%, 23%, and 33% in the subjects with the ABCB1 3435 TT, CT, and CC genotypes, respectively. Thus, quetiapine increases the plasma concentrations of (R)-methadone, possibly in part by an interaction with CYP2D6 and/or with the P-glycoprotein transporter system. No signs of overmedication caused by increased methadone plasma concentrations were noticed by the staff or reported by the patients.

Topics: Adult; Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 Enzyme System; Dibenzothiazepines; Drug Interactions; Female; Humans; Isoenzymes; Male; Methadone; Middle Aged; Narcotics; Opioid-Related Disorders; Organic Anion Transporters; Phenotype; Polymorphism, Genetic; Quetiapine Fumarate; Stereoisomerism

To determine the utility of quetiapine in a population undergoing ambulatory detoxification from opioids.. Medications utilized in our outpatient clinic for opioid withdrawal were evaluated for quality-assurance purposes. The treatment regimen generally included clonidine, hydroxyzine, trazodone, diphenoxylate/atropine, and sometimes chlordiazepoxide. Patients were also initially given eight 25-mg tablets of quetiapine and instructed to take 1 or 2 tablets every 4 hours as needed for symptoms of withdrawal or craving (with a maximum daily dose of 200 mg). Data were based on patient evaluations from June 2003 to June 2004.. 41% of all patients (N = 213) successfully completed the detoxification phase of the program (i.e., completed at least 5 days of abstinence). A medication questionnaire was instituted for quality-assurance purposes after some apparent initial success with quetiapine. A retrospective analysis of these data revealed that, of the 107 patients evaluated for medication response, 79 reported that quetiapine helped reduce craving for opioids, 52 reported that quetiapine helped reduce their anxiety, 24 reported a reduction in somatic pain, 22 reported that quetiapine helped alleviate insomnia, and 14 reported an improved appetite. Four individuals did not feel quetiapine had any benefit, and another 7 were unable to tolerate quetiapine because of side effects. The quetiapine dose used ranged from 25 to 600 mg/day (mean +/- SD dose = 206 +/- 122 mg/day).. Quetiapine use during opioid cessation was found to help abate symptoms of opioid withdrawal in our patient population and was generally well tolerated.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Behavior, Addictive; Dibenzothiazepines; Drug Administration Schedule; Drug Therapy, Combination; Female; Health Status; Humans; Male; Opioid-Related Disorders; Quality Assurance, Health Care; Quetiapine Fumarate; Retrospective Studies; Substance Withdrawal Syndrome; Surveys and Questionnaires; Treatment Outcome

Methadone and buprenorphine have pharmacologic properties that are concerning for a high risk of drug-drug interactions (DDIs). We performed high-throughput screening for clinically relevant DDIs with methadone or buprenorphine by combining pharmacoepidemiologic and pharmacokinetic approaches. We conducted pharmacoepidemiologic screening via a series of self-controlled case series studies (SCCS) in Optum claims data from 2000 to 2019. We included persons 18 years or older who experienced an outcome of interest during target drug treatment. Exposures were all overlapping medications (i.e., the candidate precipitants) during target drug treatment. Outcomes were opioid overdose, non-overdose adverse effects, and cardiac arrest. We used conditional Poisson regression to calculate rate ratios, accounting for multiple comparisons with semi-Bayes shrinkage. We explored the impact of key study design choices in analyses that varied the exposure definitions of the target drugs and the candidate precipitant drugs. Pharmacokinetic screening was conducted by incorporating published data on CYP enzyme metabolism into an equation-based static model. In SCCS analysis, 1,432 events were included from 248,069 new users of methadone or buprenorphine. In the primary analysis, statistically significant DDIs included gabapentinoids with either methadone or buprenorphine; baclofen with methadone; and benzodiazepines with methadone. In sensitivity analysis, additional statistically significant DDIs included methocarbamol, quetiapine, or simvastatin with methadone. Pharmacokinetic screening identified two moderate-to-strong potential DDIs (clonidine and fluconazole with buprenorphine). The combination of clonidine and buprenorphine was also associated with a significantly increased risk of opioid overdose in pharmacoepidemiologic screening. These DDI signals may be the most important targets for future confirmation studies.

Topics: Baclofen; Bayes Theorem; Benzodiazepines; Buprenorphine; Clonidine; Drug Interactions; Fluconazole; Humans; Methadone; Methocarbamol; Opiate Overdose; Opiate Substitution Treatment; Opioid-Related Disorders; Quetiapine Fumarate; Simvastatin